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PubMed1990

Experimental neonatal syphilis in a susceptible (C4D) and a resistant (Albany) strain of guinea pig.

Despite similar levels of natural antibodies and treponemicidal activity, 83% of fourth complement component-deficient (C4D) mother guinea pigs developed ulcerative lesions to a challenge of 5 x 10(7) Treponema pallidum, whereas 75% of offspring 1 to 5 days old were temporarily (2-3 months) resistant to development of dermal lesions. In contrast, only 17% of Albany-strain mothers developed small papular lesions, while 68% of 1- to 5-day-old newborns developed large papular or ulcerative lesions within 9-15 days postinfection. These findings, together with the late development of both dermal lesions and antibodies in C4D neonates, preclude the concept of an antibody-associated natural resistance. T. pallidum infection in either C4D or Albany neonates was not associated with depletion of any particular cell population in lymphoid tissue. However, marked age- and strain-dependent histologic differences were noted. Histologic examination of lymph nodes and spleens from 17-day-old and 3- to 4-month-old animals showed that maturation of lymphoid tissues in C4D animals lagged behind the Albany strain at either age. Moreover, 75% of C4D newborns contained significantly higher levels of immunomodulatory alpha 1 fetoprotein than Albany neonates. The possibility that differences in susceptibility to T. pallidum infection between C4D and Albany guinea pigs as neonates and again as adults is the result of genetically associated changes in immunologic recognition is discussed.

Animals↗
PubMed1996

Complement activation by 3-mercapto-1,2-propanediol immobilized on gold surfaces.

Thiol-modified surfaces are chemically well defined and suited for surface biological model experiments and biomaterials research. 3-Mercapto-1,2-propanediol (mercaptoglycerol, MG), immobilized on gold, spontaneously binds immunoglobulins from human serum and activates the complement system. The surface-bound complement factors were detected by ellipsometry-antibody techniques. The overall complement activation was subsequently corroborated independently with enzyme immunosorbent assay (EIA) and sheep and chicken erythrocyte haemolytic complement techniques. EIA experiments indicated elevated levels of C4d, but no significant increase of factor Bb was evident in the test serum from the MG system. The haemolytic assays show that MG surfaces consume complement factors from both pathways. Ellipsometry revealed that immunoglobulin G (IgG) and complement factor 1q (C1q) are transiently antibody detectable on MG after exposure to whole serum by the use of antibody techniques. Complement factor 3 (C3), C2, C4 and properdin could be detected on the surface, but not factors H and B. The total adsorbed mass and particularly C3 antibody deposition were suppressed by using EGTA-Mg2+ serum. The results suggest that MG surfaces initially activate complement via the classical pathway. Other IgG binding surfaces also appear to behave in a similar manner.

Animals↗
PubMed1983

Cleavage of membrane-bound C3b and C3bi by viable human neutrophils (PMN).

Cleavage of C3 by purified leukocyte enzymes and crude extracts of human polymorphonuclear leukocyte (PMN) granules has been reported. We demonstrate that viable PMN mediate the cleavage of erythrocyte-bound C3b and C3bi via cell-associated proteases. Greater than 50% of 125IC3(x) was released from EAC43bix during a 5-min incubation with viable PMN at 37 degrees C. More than a 30-min incubation was required for substantial release from EAC43bx. Culture fluids from PMN suspensions had limited cleaving ability; cleavage of cell-bound C3bx and C3bix was only partially reduced when PMN were preincubated with high levels of soluble C3 which completely blocked EAC43b rosettes. Thus, cell-to-cell contact between opsonized erythrocytes and viable PMN with surface-associated proteases are responsible for cleavage of these opsonic sites. The effect of defined protease inhibitors on PMN cleaving activity as well as on purified leukocyte elastase was examined. Phenylmethylsulfonyl fluoride (PMSF) and the leukocyte elastase inhibitor, methoxy-succinate-alanine-alanine-valine-chloromethyl ketone (MeO) each inhibited cleavage of C3b by 90% and C3bi by 60%. In contrast, the cathepsin-G inhibitor, benzyloxy-carbonyl-glycine-leucine-phenylalanine-chloromethyl ketone (Z) inhibited C3b and C3bi cleavage by less than 20 and less than 5%, respectively. Ethylenediaminetetra-acetate (EDTA), which had a minimal effect on soluble leukocyte elastase, also inhibited PMN-related release. Thus, elastase appeared to be the principle but not the only enzyme responsible for cleavage of C3b and C3bi. PMSF and MeO had a minimal effect on the activity of purified C3bINA (Factor I); and PMN-mediated release of C3b fragments was not inhibited by anti-Factor I and anti-beta 1H (Factor H) IgG and Fab. Thus, these control proteins are not involved in the PMN-mediated cleavage under study. PMN-mediated cleavage of C3b was also inhibited when PMSF- and MeO-treated PMN were washed to remove the fluid phase phase protease inhibitor before adding EAC43b. This suggests that proteases localized in the PMN membrane, prior to the adherence of EAC43b, are responsible for C3b cleavage. Normal human serum was effective in blocking PMN-mediated release activity, while serum from alpha 1 antitrypsin-deficient patients was minimally effective. This suggests a mechanism for the in vivo regulation of PMN-mediated release of C3b and C3bi from opsonized particles by the natural plasma protease inhibitors.

Amino Acid Chloromethyl Ketones↗
PubMed1987

A monoclonal antibody which can distinguish between the two isotypes of human C4.

A monoclonal antibody to Human C4 (L003) has been shown to bind to the polymorphic C4d fragment of the alpha-chain of C4. Another monoclonal antibody (L001) was shown to bind to the beta-chain. L003 reacts differently with the two isotypes of C4, C4-A and C4-B. The equilibrium constant of L003 for C4-B is approx. 7-fold higher than that for C4-A, while L001 has similar affinity for both C4 types. Also, L003 binding to C4-A is very much more pH dependent than is its binding to C4-B. These observations explain the very useful property of L003 in being able to separate the two isotypes by affinity chromatography.

Antibodies, Monoclonal↗
PubMed1988

Association of complement allotype C4B2 with anterior uveitis.

We have studied allotypes of the fourth component of complement (C4) in 44 patients with inflammatory eye disease in order to define genetic susceptibility factors further. Twenty-six patients had uveitis (18 had anterior uveitis) and 18 patients had retinal vasculitis. There was an increased incidence of the C4B2 allotype in patients with anterior uveitis (pc less than 0.002), especially in HLA B27 positive males. In contrast, there was no increased incidence of specific allotypes in patients with posterior uveitis or retinal vasculitis. This genetic association may form part of a disease susceptibility supratype in patients with anterior uveitis.

Alleles↗
PubMed1990

Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement proteins C3d and C4d.

Clusters of oligodendroglial fibers were identified immunohistochemically in human brain tissue with antibodies to the complement proteins C3d and C4d in several neurological disorders. These included Pick's, Huntington's, Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy and Shy-Drager syndrome. These complement-activated oligodendroglia occurred in selected areas of gray and white matter. They were rarely observed in control tissue. Immunogold electron microscopy established that the C4d antibody was attached to degenerating myelin sheaths. These data indicate attachment of classical complement pathway proteins to selective oligodendroglia in several neurological disorders.

Brain Diseases↗
PubMed1995

Chronically administered 3-nitropropionic acid induces striatal lesions attributed to dysfunction of the blood-brain barrier.

3-Nitropropionic acid (3-NPA), an irreversible inhibitor of succinate dehydrogenase, was administered to rats and the characteristics of the neuronal damage were investigated. Injections of 3-NPA (15 mg/kg s.c.) every 2 or 3 days for 1-2 weeks induced a mild neuronal loss and neutrophil invasions in the striatum (STR). The same administration for 4 weeks induced specific symmetric lesions in the lateral STR although the size was variable in each animal. Inside the lesions, strong neutrophil invasions and a strong immunoreaction for IgG, C3 as well as complement factor C3b/C4b receptor (C3b/C4br) were detected. Lesioned sites lost the immunoreaction for GFAP while the marginal areas contained abundant GFAP-labeled astrocytes around the vessels. In intoxicated animals, there was a weak but stout immunoreaction for IgG and C3b/C4br localizing around vessels in the STR even when there were no lesions or neuronal loss. The data suggest that the blood-brain barrier dysfunction is responsible for the specific vulnerability of the STR for the toxin.

Animals↗
PubMed2004

C4BQ0: a genetic marker of familial HCV-related liver cirrhosis.

BACKGROUND AND METHODS: Host may have a role in the evolution of chronic HCV liver disease. We performed two cross-sectional prospective studies to evaluate the prevalence of cirrhosis in first degree relatives of patients with cirrhosis and the role of two major histocompatibility complex class III alleles BF and C4 versus HCV as risk factors for familial clustering. FINDINGS: Ninety-three (18.6%) of 500 patients with cirrhosis had at least one cirrhotic first degree relative as compared to 13 (2.6%) of 500 controls, (OR 7.38; CI 4.21-12.9). C4BQ0 was significantly more frequent in the 93 cirrhotic patients than in 93 cirrhotic controls without familiarity (Hardy-Weinberg equilibrium: chi2 5.76, P = 0.016) and in 20 families with versus 20 without aggregation of HCV related cirrhosis (29.2% versus 11.3%, P = 0.001); the association C4BQ0-HCV was found almost only in cirrhotic patients with a family history of liver cirrhosis. CONCLUSIONS: Our studies support the value of C4BQ0 as a risk indicator of familial HCV related cirrhosis.

Adolescent↗
PubMed2005

C4d deposition in cardiac allografts correlates with alloantibody.

BACKGROUND: The presence of C4d along the peritubular capillaries in kidney allografts correlates with the presence of anti-donor serum alloantibodies. We applied C4d staining to cardiac allograft and non-allograft biopsies to determine if C4d staining in heart allografts correlates with anti-donor serum alloantibodies. METHODS: We stained for C4d all available frozen tissue biopsies from cardiac transplant recipients between 1997 and 2002, including autopsies. Two hundred twenty-one tissue samples from 124 patients were analyzed. Included in both groups were a variety of International Society for Heart and Lung Transplantation (ISHLT) grades of rejection plus post-implant cardiac ischemic injury (PIMI), and biopsies from patients who had received OKT3. Patients were matched by age, gender and interval after transplantation. Forty-four additional controls were included from patients biopsied for non-transplant-related cardiac disease. RESULTS: C4d staining of the myocardial capillaries correlated well with the presence of anti-donor alloantibodies. Twenty-one of 25 biopsies from patients with anti-donor alloantibodies showed C4d staining (84%), whereas only 7 of 60 without anti-donor alloantibodies stained for C4d. C4d staining did not correlate with ischemia or OKT3 therapy. Only 4 of 44 non-transplant biopsies stained for C4d (9%). An example of the clinical utility of C4d staining in patient care is presented. CONCLUSIONS: C4d staining of the capillaries in cardiac allografts correlates well with anti-donor serum alloantibodies, is a useful assay to verify alloantibody deposition, and can be used to establish one of the criteria for antibody-mediated cardiac rejections.

Biomarkers↗
PubMed2005

C4d staining of pulmonary allograft biopsies: an immunoperoxidase study.

BACKGROUND: The role of antibody-mediated/humoral rejection in lung allografts is not fully elucidated. In other organ systems, deposition of a specific complement product, C4d, is a sensitive and specific marker for humoral rejection. C4d can be evaluated in tissue biopsies by immunofluorescence or light microscopic immunohistochemical staining techniques. Using immunohistochemical staining techniques we sought to determine whether there was any specific staining pattern for C4d in lung allograft biopsies with or without the diagnosis of acute or chronic cellular or humoral rejection. METHODS: A total of 68 lung transplant biopsies, performed at UCLA Medical Center from January 2002 to August 2004, were collected and the paraffin blocks were re-cut and stained for C4d by an immunoperoxidase technique. The cases were separated by the presence or absence of features of acute and/or chronic rejection based on the International Society for Heart and Lung Transplantation working formulation for the classification of pulmonary allograft rejection, revised 1995. The pattern of staining for C4d was then systematically examined. RESULTS: Positive staining in a variable, focal non-specific pattern was observed. There was no consistent staining pattern within the different diagnostic groups. CONCLUSIONS: C4d staining of paraffin-embedded lung allograft biopsies, using currently available techniques, does not identify acute or chronic cellular or humoral rejection in lung allograft tissue.

Acute Disease↗
PubMed2005

The role of complement in myasthenia gravis: serological evidence of complement consumption in vivo.

BACKGROUND: Antibodies to the acetylcholine receptor (AChR) titin and the ryanodine receptor (RyR) occur in myasthenia gravis (MG). These antibodies are capable of complement activation in vitro. The involvement of the complement system should cause consumption of complement components such as C3 and C4 in vivo. MATERIALS AND METHODS: Complement components C3 and C4 were assayed in sera from 78 AChR antibody-positive MG patients and 52 healthy controls. Forty-eight of the patient sera contained titin antibodies as well, and 20 were also RyR antibody-positive. RESULTS: MG patients with AChR antibody concentrations above the median (11.2 nmol/l) had significantly lower mean C3 and C4 concentrations in serum compared to those with AChR antibody concentrations below the median. Titin antibody-positive MG patients, titin antibody-negative early-onset MG patients, titin antibody-negative late-onset MG patients, and controls had similar C3 and C4 concentrations. Nor did mean C3 and C4 concentrations differ in MG patients with RyR antibodies. Patients with severe MG (grades 4 and 5) had similar C3 and similar C4 levels compared to those with mild MG (grades 1 and 2). CONCLUSION: An increased in vivo complement consumption was detected in MG patients with high AChR antibody concentrations, unrelated to MG severity and non-AChR muscle antibodies.

Antibodies↗
PubMed2005

Phosphodiesterase type 4 inhibitor rolipram inhibits activation of monocytes during extracorporeal circulation.

OBJECTIVE: Cardiopulmonary bypass is associated with systemic inflammatory response syndrome and risk of multiorgan injury mediated by activated leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in leukocytes and plays a key role in the regulation of leukocyte activation. The aim of this study was to examine the effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on functional changes of monocytes during simulated extracorporeal circulation. METHODS AND RESULTS: Simulated extracorporeal circulation was established by recirculating heparinized human blood for 120 minutes on a membrane oxygenator with or without 10 micromol/L of rolipram. L-selectin and CD11b expression of monocytes were measured with flow cytometry. C4d fragment, Bb fragment, C5b-9, and interleukin-6 were measured with enzyme immunoassay. Rolipram reduced the increase in CD11b expression and the decrease in L-selectin expression of monocytes in response to simulated extracorporeal circulation. Rolipram inhibited the increase in C4d fragment and interleukin-6, but it did not affect the increase in Bb fragment or C5b-9. CONCLUSION: Rolipram inhibited changes in adhesion molecule expression and interleukin-6 release by activated monocytes in simulated extracorporeal circulation. This study suggests that phosphodiesterase type 4 inhibition could be feasible therapeutic strategy to prevent exaggerated inflammatory response and organ injury in patients undergoing cardiopulmonary bypass.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Diagnostic value of C4d in renal allograft biopsies in different clinical settings: absence of C4d in grafts from non-heart-beating donors.

UNLABELLED: Humoral mechanisms of rejection after kidney transplantation (TX) can be identified through the detection of diffuse complement C4d deposits in peritubular capillaries (PTC) in graft biopsies or donor-specific antibodies (DSA) in serum samples. It has been hypothesized that ischemic injury in the graft may facilitate humoral responses. Kidney grafts from non-heart-beating donors (NHBD) present more often severe ischemia lesions than grafts from heart-beating or living donors. METHODS: We reviewed kidney TX biopsies performed from May 2002 to November 2004 with special interest paid to recipients from NHBD. We checked corresponding frozen tissue for the detection of C4d in PTC using immunofluorescence with a monoclonal antibody against C4d. We also collected post-TX contemporaneous DSA data, either flow crossmatches or cytotoxic PRA. RESULTS: During this period, we performed 22 kidney TXs from NHBD of a total of 326 kidney TX (either single or combined with other grafts). Nine patients of this group underwent 12 biopsies for delayed graft function over 15 days or deteriorating scans. All biopsies showed acute tubular necrosis, but one also presented IA Banff acute rejection and another one had neutrophils in PTC. Frozen tissue from these 12 biopsies did not have diffuse C4d deposits in PTC. Serum samples of seven of nine patients were available: four had negative DSA flow crossmatches and three had 0% PRA within the same period. We diagnosed acute humoral rejection (AHR) in 13 patients-with acute renal dysfunction, C4d in biopsies and DSA after kidney TX-of 38 with high clinical suspicion for AHR. We detected C4d in seven biopsies of 30 patients performed more than 6 months after TX. CONCLUSIONS: Severe ischemic injury does not necessarily determine the activation of humoral mechanisms of rejection mediated through DSA. Therefore, C4d is extremely interesting for the identification of humoral rejection in any clinical setting after kidney TX.

Antibody Formation↗
PubMed2005

Late developing C4d-positive humoral renal allograft rejection associated with withdrawal of mycophenolate mofetil.

In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body's humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.

Acute Disease↗
PubMedDate not supplied

C4d complement split product in diagnosis of immunological activity of chronic allograft nephropathy.

INTRODUCTION: Activation of the humoral branch of the immunological response is currently believed to play an important role in pathogenesis of chronic allograft nephropathy. The impact of humoral alloreactivity, indicated by the presence of C4d deposits in peritubular capillaries of a renal allograft, on the development of chronic allograft nephropathy is a significant problem in transplantation. The aim of the study was to assess and correlate C4d expression in patients with chronic allograft nephropathy, with clinical and morphological variables, as well as to assess the impact of a change in immunosuppression regimen on posttransplant course and renal allograft morphology. PATIENTS AND METHODS: Twenty-six patients with chronic allograft nephropathy underwent biopsies to correlate C4d expression with clinical parameters and morphological findings. In all patients azathioprine was replaced with mycophenolate mofetil with additional CsA dose reduction in 12 patients. After 1 year, 14 protocol biopsies were performed. RESULTS: The frequency of C4d peritubular capillary deposition among patients with chronic allograft nephropathy was 30%. C4d expression appeared later after transplantation, was correlated with chronic allograft glomerulopathy and proteinuria but not other clinical or histological variables. C4d deposits displayed no independent impact on serum creatinine level. Proteinuria was significantly more reduced in the C4d(+) group. Progression of chronic morphological changes was significantly accelerated in the C4d(+) group. CONCLUSION: C4d peritubular capillary expression did not differentiate patients after immunosuppression enhancement, but it predisposed to progression of chronic morphological findings during 1-year observation.

Adult↗
PubMed2006

C4d: a marker for hepatic transplant rejection.

BACKGROUND: Acute rejection is still a common complication of hepatic transplantation. The diagnosis, based on the histological examination of the graft, may be difficult to confirm in the setting of combined hepatitis C virus infection. The presence of C4d in the portal capillaries could facilitate differentiation between acute rejection and relapsed hepatitis C. The deposit of C4d provides evidence of activation of humoral immunity. To attempt to confirm this hypothesis, we searched for the presence of C4d in posttransplant hepatic biopsies. METHODS: Thirty-six biopsies from 34 patients were analyzed retrospectively. The samples had been requested for one of the following reasons: suspected rejection, relapsed hepatitis C infection, or systematic check-up 1 year after the transplant. RESULTS: C4d expression was common in biopsies classified as acute rejection (33%) and chronic rejection (100%). C4d was never detected in the event of recurrent hepatitis C infection without rejection. CONCLUSION: These results, which are comparable to recently published data, give credence to the theory that C4d could be used as a marker for rejection following hepatic transplantation.

Acute Disease↗